Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA.
Department of Kinesiology and Physical Education, McGill University, Montreal, Quebec, Canada.
J Cachexia Sarcopenia Muscle. 2022 Feb;13(1):589-604. doi: 10.1002/jcsm.12826. Epub 2021 Nov 1.
Chronic obstructive pulmonary disease (COPD) patients exhibit skeletal muscle atrophy, denervation, and reduced mitochondrial oxidative capacity. Whilst chronic tobacco smoke exposure is implicated in COPD muscle impairment, the mechanisms involved are ambiguous. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that activates detoxifying pathways with numerous exogenous ligands, including tobacco smoke. Whereas transient AHR activation is adaptive, chronic activation can be toxic. On this basis, we tested the hypothesis that chronic smoke-induced AHR activation causes adverse muscle impact.
We used clinical patient muscle samples, and in vitro (C2C12 myotubes) and in vivo models (mouse), to perform gene expression, mitochondrial function, muscle and neuromuscular junction morphology, and genetic manipulations (adeno-associated virus-mediated gene transfer).
Sixteen weeks of tobacco smoke exposure in mice caused muscle atrophy, neuromuscular junction degeneration, and reduced oxidative capacity. Similarly, smoke exposure reprogrammed the muscle transcriptome, with down-regulation of mitochondrial and neuromuscular junction genes. In mouse and human patient specimens, smoke exposure increased muscle AHR signalling. Mechanistically, experiments in cultured myotubes demonstrated that smoke condensate activated the AHR, caused mitochondrial impairments, and induced an AHR-dependent myotube atrophy. Finally, to isolate the role of AHR activity, expression of a constitutively active AHR mutant without smoke exposure caused atrophy and mitochondrial impairments in cultured myotubes, and muscle atrophy and neuromuscular junction degeneration in mice.
These results establish that chronic AHR activity, as occurs in smokers, phenocopies the atrophy, mitochondrial impairment, and neuromuscular junction degeneration caused by chronic tobacco smoke exposure.
慢性阻塞性肺疾病（COPD）患者表现出骨骼肌萎缩、去神经支配和线粒体氧化能力降低。虽然慢性烟草烟雾暴露与 COPD 肌肉损伤有关，但涉及的机制尚不清楚。芳香烃受体（AHR）是一种配体激活的转录因子，可激活多种外源性配体（包括烟草烟雾）的解毒途径。虽然 AHR 的瞬时激活是适应性的，但慢性激活可能是有毒的。在此基础上，我们检验了这样一个假设，即慢性烟雾诱导的 AHR 激活导致不良的肌肉影响。
我们使用临床患者肌肉样本，以及体外（C2C12 肌管）和体内模型（小鼠），进行基因表达、线粒体功能、肌肉和神经肌肉接头形态以及基因操作（腺相关病毒介导的基因转移）。
16 周的烟草烟雾暴露在小鼠中引起肌肉萎缩、神经肌肉接头退化和氧化能力降低。同样，烟雾暴露重新编程了肌肉转录组，导致线粒体和神经肌肉接头基因下调。在小鼠和人类患者标本中，烟雾暴露增加了肌肉 AHR 信号。在机制上，培养的肌管实验表明，烟雾冷凝物激活了 AHR，导致线粒体损伤，并诱导了 AHR 依赖性肌管萎缩。最后，为了分离 AHR 活性的作用，在没有烟雾暴露的情况下表达一种组成型激活的 AHR 突变体，在培养的肌管中引起萎缩和线粒体损伤，并在小鼠中引起肌肉萎缩和神经肌肉接头退化。
这些结果表明，慢性 AHR 活性，如在吸烟者中发生的那样，模拟了由慢性烟草烟雾暴露引起的萎缩、线粒体损伤和神经肌肉接头退化。
